ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation

Christian W. Keller, Christina Sina, Monika B. Kotur, Giulia Ramelli, Sarah Mundt, Isaak Quast, Laure Anne Ligeon, Patrick Weber, Burkhard Becher, Christian Münz, Jan D. Lünemann

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Abstract

Although reactivation and accumulation of autoreactive CD4+ T cells within the CNS are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the mechanisms of how these cells recognize their target organ and induce sustained inflammation are incompletely understood. Here, we report that mice with conditional deletion of the essential autophagy protein ATG5 in classical dendritic cells (DCs), which are present at low frequencies in the nondiseased CNS, are completely resistant to EAE development following adoptive transfer of myelin-specific T cells and show substantially reduced in situ CD4+ T cell accumulation during the effector phase of the disease. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserineexposing oligodendroglial cells is abrogated in the absence of ATG5. Pharmacological inhibition of ATG-dependent phagocytosis by the cardiac glycoside neriifolin, an inhibitor of the Na+, K+-ATPase, delays the onset and reduces the clinical severity of EAE induced by myelin-specific CD4+ T cells. These findings link phagocytosis of injured oligodendrocytes, a pathological hallmark of MS lesions and during EAE, with myelin antigen processing and T cell pathogenicity, and identify ATG-dependent phagocytosis in DCs as a key regulator in driving autoimmune CD4+ T cell-mediated CNS damage.

Original languageEnglish
Pages (from-to)E11228-E11237
Number of pages10
JournalProceedings of the National Academy of Sciences
Volume114
Issue number52
DOIs
Publication statusPublished - 26 Dec 2017

Keywords

  • Autophagy
  • EAE
  • Multiple sclerosis
  • Neuroinflammation

Cite this

Keller, Christian W. ; Sina, Christina ; Kotur, Monika B. ; Ramelli, Giulia ; Mundt, Sarah ; Quast, Isaak ; Ligeon, Laure Anne ; Weber, Patrick ; Becher, Burkhard ; Münz, Christian ; Lünemann, Jan D. / ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation. In: Proceedings of the National Academy of Sciences. 2017 ; Vol. 114, No. 52. pp. E11228-E11237.
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abstract = "Although reactivation and accumulation of autoreactive CD4+ T cells within the CNS are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the mechanisms of how these cells recognize their target organ and induce sustained inflammation are incompletely understood. Here, we report that mice with conditional deletion of the essential autophagy protein ATG5 in classical dendritic cells (DCs), which are present at low frequencies in the nondiseased CNS, are completely resistant to EAE development following adoptive transfer of myelin-specific T cells and show substantially reduced in situ CD4+ T cell accumulation during the effector phase of the disease. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserineexposing oligodendroglial cells is abrogated in the absence of ATG5. Pharmacological inhibition of ATG-dependent phagocytosis by the cardiac glycoside neriifolin, an inhibitor of the Na+, K+-ATPase, delays the onset and reduces the clinical severity of EAE induced by myelin-specific CD4+ T cells. These findings link phagocytosis of injured oligodendrocytes, a pathological hallmark of MS lesions and during EAE, with myelin antigen processing and T cell pathogenicity, and identify ATG-dependent phagocytosis in DCs as a key regulator in driving autoimmune CD4+ T cell-mediated CNS damage.",
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Keller, CW, Sina, C, Kotur, MB, Ramelli, G, Mundt, S, Quast, I, Ligeon, LA, Weber, P, Becher, B, Münz, C & Lünemann, JD 2017, 'ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation', Proceedings of the National Academy of Sciences, vol. 114, no. 52, pp. E11228-E11237. https://doi.org/10.1073/pnas.1713664114

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation. / Keller, Christian W.; Sina, Christina; Kotur, Monika B.; Ramelli, Giulia; Mundt, Sarah; Quast, Isaak; Ligeon, Laure Anne; Weber, Patrick; Becher, Burkhard; Münz, Christian; Lünemann, Jan D.

In: Proceedings of the National Academy of Sciences, Vol. 114, No. 52, 26.12.2017, p. E11228-E11237.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Keller, Christian W.

AU - Sina, Christina

AU - Kotur, Monika B.

AU - Ramelli, Giulia

AU - Mundt, Sarah

AU - Quast, Isaak

AU - Ligeon, Laure Anne

AU - Weber, Patrick

AU - Becher, Burkhard

AU - Münz, Christian

AU - Lünemann, Jan D.

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